Fluconazole

Fluconazole is an antifungal agent belonging to the pharmacological class of Azole Antifungal Derivatives

Fluconazole has been approved to relieve symptoms and also for the treatment and maintenance of Blastomycosis, Candidiasis, treatment, Candidiasis, prophylaxis, Coccidioidomycosis, treatment, Coccidioidomycosis, prophylaxis, Cryptococcal meningitis, Cryptococcosis, pulmonary infection, Onychomycosis, Tinea infections.

Orally administered fluconazole has a bioavailability of over 90% in healthy volunteers and is extensively absorbed in the gastrointestinal tract. Fluconazole has a volume of distribution similar to total body water, and it penetrates various body fluids, making it effective for systemic fungal infections. It accumulates in the skin, particularly in the stratum corneum, which is beneficial for superficial fungal infections. Concentrations in saliva, sputum, and cerebrospinal fluid (CSF) are similar to plasma levels, indicating good penetration across different barriers. Metabolism of fluconazole is minimal in the liver, but it inhibits several cytochrome P450 enzymes. The majority of fluconazole is cleared through renal excretion, with approximately 80% of the administered dose found unchanged in the urine.

The common side effects involved in using Fluconazole are Nausea, Headache, Abdominal pain, Diarrhea, Vomiting, Rash, Dizziness, Fatigue, Changes in taste sensation, Upset stomach, Indigestion

Fluconazole is available in the form of Oral tablets, Oral suspensions, and Intravenous injections.

Fluconazole is approved in Germany, Japan, Malaysia, India, the U.K., the U.S., and China.

Fluconazole belongs to the pharmacological class of Azole Antifungal Derivatives

Fluconazole exhibits a high degree of selectivity as it specifically inhibits the activity of the fungal enzyme lanosterol 14-α-demethylase, which is part of the cytochrome P450 system. This enzyme plays a crucial role in converting lanosterol into ergosterol, an essential component for the synthesis of fungal cell walls. By binding to the iron atom in the heme group of lanosterol 14-α-demethylase, fluconazole's azole ring effectively blocks the activation of oxygen, preventing the demethylation of lanosterol. Consequently, the biosynthesis of ergosterol is halted, leading to the accumulation of methylated sterols within the fungal cell membrane. This accumulation adversely affects the structure and function of the fungal cell plasma membrane, resulting in the inhibition of fungal growth.

Fluconazole has been approved to relieve symptoms and also for the treatment and maintenance of Blastomycosis, Candidiasis, treatment, Candidiasis, prophylaxis, Coccidioidomycosis, treatment, Coccidioidomycosis, prophylaxis, Cryptococcal meningitis, Cryptococcosis, pulmonary infection, Onychomycosis, Tinea infections.

In fasting and healthy volunteers, the highest levels of fluconazole in the blood (peak plasma concentrations or Cmax) are reached approximately 1-2 hours after taking the dose. It takes about 5 to 10 days of once-daily oral dosing with 50-400 mg of fluconazole to achieve steady-state concentrations. By administering a higher initial dose (loading dose) on the first day of treatment, or twice the usual daily dose, the plasma concentrations of fluconazole approach steady-state levels by the second day. In healthy volunteers receiving 25 mg of fluconazole, the average AUC (area under the curve) was measured to be 20.

In individuals who are fasting and in good health, the highest levels of fluconazole in the blood (peak plasma concentrations or Cmax) are typically observed around 1 to 2 hours after taking the medication. It takes approximately 5 to 10 days of daily oral doses ranging from 50 to 400 mg to reach stable concentrations in the bloodstream (steady-state concentrations)

Fluconazole is found to be available in the form of Oral tablets, Oral suspensions, and Intravenous injections.

Fluconazole can be used in the following treatment:

• Blastomycosis
• Candidiasis, treatment
• Candidiasis, prophylaxis
• Coccidioidomycosis, treatment
• Coccidioidomycosis, prophylaxis
• Cryptococcal meningitis
• Cryptococcosis, pulmonary infection
• Onychomycosis

Fluconazole can help to relieve symptoms and also for the treatment and maintenance of Blastomycosis, Candidiasis, treatment, Candidiasis, prophylaxis, Coccidioidomycosis, treatment, Coccidioidomycosis, prophylaxis, Cryptococcal meningitis, Cryptococcosis, pulmonary infection, Onychomycosis, Tinea infections.

Fluconazole is approved for use in the following clinical indications:

• Blastomycosis
• Candidiasis, treatment
• Candidiasis, prophylaxis
• Coccidioidomycosis, treatment
• Coccidioidomycosis, prophylaxis
• Cryptococcal meningitis
• Cryptococcosis, pulmonary infection
• Onychomycosis
• Tinea infections

• Blastomycosis:
• Initial treatment: 200-400 mg daily
• Maintenance treatment: 100-200 mg daily
• Candidiasis, treatment:
• Oropharyngeal candidiasis: 200 mg on the first day, followed by 100 mg daily for at least 2 weeks
• Esophageal candidiasis: 200 mg on the first day, followed by 100-200 mg daily for at least 3 weeks
• Systemic candidiasis: 400 mg daily; duration varies depending on the infection site and severity
• Candidiasis, prophylaxis:
• In patients with bone marrow transplant: 400 mg daily, starting a few days before the transplant and continuing until neutropenia resolves
• In patients undergoing hematopoietic stem cell transplantation: 400 mg daily, starting 7 days before the transplant and continuing until neutropenia resolves
• Coccidioidomycosis, treatment:
• Acute pulmonary infection: 200-400 mg daily; duration varies depending on the severity of the infection
• Disseminated infection: 400 mg daily; duration varies depending on the site and severity of the infection
• Coccidioidomycosis, prophylaxis:
• In patients undergoing hematopoietic stem cell transplantation: 400 mg daily, starting 7 days before the transplant and continuing until engraftment
• Cryptococcal meningitis:
• Induction therapy: 400 mg on the first day, followed by 200-400 mg daily for at least 10-12 weeks
• Consolidation therapy: 200-400 mg daily for an additional 8 weeks
• Maintenance therapy: 200 mg daily for long-term suppression in patients with AIDS
• Cryptococcosis, pulmonary infection:
• 200-400 mg daily, duration varies depending on the site and severity of the infection
• Onychomycosis:
• 150 mg once weekly for 6-12 months, depending on the extent of nail involvement
• Tinea infections:
• 150 mg once weekly for 2-6 weeks, depending on the type and location of the infection

Oral Tablet: 50 mg, 100 mg, 150 mg, and 200 mg

Oral Suspension: 10 mg/mL

Intravenous (IV) Injection: 2 mg/mL

• Dosage Adjustments in Kidney Patients:

If the creatinine clearance (CrCl) is greater than 50 mL/minute, no dosage adjustment is necessary.

If the CrCl is equal to or less than 50 mL/minute, reduce the dose by 50%.

• Dosage Adjustments in Hepatic Impairment Patients:

No dosage adjustments are necessary.

• Dosage Adjustments in Pediatric Patients:
• Candida Infections, Prophylaxis:
• Neonates: The recommended dosage is 3-6 mg/kg/dose given every 72 hours.
• Infants and Children: The recommended dosage is 3-12 mg/kg/dose given every 72 hours.
• Candidiasis, Systemic, Treatment:
• Neonates: The recommended dosage is 6-12 mg/kg/dose given every 72 hours.
• Infants and Children: The recommended dosage is 6-12 mg/kg/dose given every 72 hours.
• Candidiasis, CNS Candidiasis, Step-Down Therapy:
• Neonates: The recommended dosage is 12 mg/kg/dose given every 72 hours.
• Infants and Children: The recommended dosage is 12 mg/kg/dose given every 72 hours.
• Candidiasis, Endophthalmitis, Treatment:
• Neonates: The recommended dosage is 6-12 mg/kg/dose given every 72 hours.
• Infants and Children: The recommended dosage is 6-12 mg/kg/dose given every 72 hours.
• Candidiasis, Esophageal:
• Neonates: The recommended dosage is 6 mg/kg/dose given every 72 hours.
• Infants and Children: The recommended dosage is 6-12 mg/kg/dose given every 72 hours.
• Candidiasis, Oropharyngeal:
• Neonates: The recommended dosage is 3 mg/kg/dose given every 72 hours.
• Infants and Children: The recommended dosage is 3-6 mg/kg/dose given every 72 hours.
• Candidiasis, Peritoneal Dialysis-Related Infections:
• Neonates: The recommended dosage is 3-6 mg/kg/dose given every 72 hours.
• Infants and Children: The recommended dosage is 3-6 mg/kg/dose given every 72 hours.
• Candidiasis, Vulvovaginal:
• Adolescents: The recommended dosage is a single 150 mg dose.
• Coccidioidomycosis, HIV-Exposed/-Infected:
• Infants and Children: The recommended dosage is 6-12 mg/kg/dose given every 72 hours.
• Cryptococcal Infection:
• Infants and Children: The recommended dosage is 12 mg/kg/dose on the first day, followed by 6 mg/kg/dose once daily.
• Histoplasmosis:
• Infants and Children: The recommended dosage is 6-12 mg/kg/dose given every 72 hours.

• Oral Tablets: These are solid tablets that are taken by mouth and swallowed with water.
• Oral Suspension: This is a liquid formulation of fluconazole that is taken by mouth. It is available in powder form, which needs to be reconstituted with water before use.
• Intravenous (IV) Injection: Fluconazole can be administered directly into a vein through an IV line. It is available as a sterile solution in vials or infusion bags. The IV formulation is used in cases where oral administration is not feasible or when a more rapid onset of action is desired.

While there are no specific dietary restrictions associated with the use of Fluconazole, it is important to note the following considerations:

• Patients who have previously demonstrated hypersensitivity to fluconazole, any of its excipients, or other azole compounds should not take Fluconazole (fluconazole).
• The concomitant use of drugs that are known to prolong the QT interval and are metabolized by the enzyme CYP3A4, such as erythromycin, pimozide, and quinidine, is contraindicated in patients receiving fluconazole.

Fluconazole may be contraindicated under the following conditions:

• Coadministration of certain CYP3A4 substrates (dofetilide, quinidine, cisapride, and pimozide) is contraindicated with Fluconazole.
• Fluconazole can increase plasma concentrations of these drugs, leading to potential therapeutic and adverse effects, including QT prolongation and life-threatening ventricular tachyarrhythmias.
• Other drugs contraindicated with Fluconazole include methadone, disopyramide, dronedarone, ergot alkaloids, irinotecan, lurasidone, oral midazolam, alprazolam, triazolam, felodipine, nisoldipine, ranolazine, tolvaptan, eplerenone, lovastatin, simvastatin, and colchicine.
• Enhanced Sedation
• Concomitant use of Fluconazole with oral midazolam, oral triazolam, or alprazolam can result in elevated plasma concentrations of these drugs.
• This may increase and prolong the hypnotic and sedative effects, especially with repeated or chronic administration.
• Coadministration with oral triazolam, oral midazolam, or alprazolam is contraindicated.
• Myopathy
• Coadministration of HMG-CoA reductase inhibitors metabolized by CYP3A4, such as simvastatin and lovastatin, is contraindicated with Fluconazole.
• Ergotism
• Concomitant administration of ergot alkaloids (dihydroergotamine and ergotamine) with Fluconazole is contraindicated.
• Liver Disease
• The use of Fluconazole is contraindicated in patients with acute or chronic liver disease.
• Hypersensitivity
• Fluconazole is contraindicated in patients who have demonstrated hypersensitivity to the drug.

• Use in Patients with Hereditary Problems:

Fluconazole Powder for Oral Suspension contains sucrose and should not be used in patients with hereditary fructose intolerance, glucose/galactose malabsorption, or sucrase-isomaltase deficiency.

• Anaphylaxis:

In rare cases, anaphylaxis (a severe allergic reaction) has been reported.

• Cardiovascular - QT Prolongation:

Fluconazole, like some other azole antifungal medications, has been associated with prolongation of the QT interval on an electrocardiogram (ECG). This can potentially lead to a specific type of dangerous heart rhythm called torsade de pointes. Rare cases of QT prolongation and torsade de pointes have been reported, especially in seriously ill patients with multiple risk factors such as structural heart disease, electrolyte abnormalities, and concurrent use of medications that can also prolong the QT interval. Caution should be exercised when using fluconazole in patients with conditions that can predispose them to proarrhythmic events, and co-administration with other drugs that prolong the QT interval should be monitored closely.

• Driving and Operating Machinery:

Occasional dizziness or seizures may occur while taking fluconazole, so caution should be exercised when driving vehicles or operating machinery.

• Endocrine and Metabolism:

Cases of adrenal insufficiency (reduced function of the adrenal glands) have been reported in patients receiving other azole antifungal medications. Reversible cases of adrenal insufficiency have also been reported in patients receiving fluconazole or upon discontinuation of fluconazole.

• CYP2C9, CYP2C19, and CYP3A4 Metabolized Drugs:

Fluconazole inhibits certain enzymes (CYP2C9, CYP2C19, and CYP3A4) involved in the metabolism of other drugs. Patients taking fluconazole along with drugs metabolized through these enzymes, especially those with a narrow therapeutic window, should be monitored closely.

• Hepatic/Biliary/Pancreatic:

Fluconazole should be used with caution in patients with liver dysfunction. Rare cases of serious hepatic toxicity, including fatalities, have been reported. The relationship between fluconazole-associated hepatotoxicity and factors such as dose, therapy duration, sex, or age of the patient is not clear. Abnormal liver function tests during fluconazole therapy should be monitored for potential severe hepatic injury, and fluconazole should be discontinued if clinical signs and symptoms of liver disease develop.

• Renal:

Fluconazole should be used with caution in patients with renal dysfunction. Dosage adjustment may be necessary.

• Reproductive Health:

Effective contraceptive measures should be considered in women of childbearing potential and continued throughout the treatment period with Fluconazole and for approximately 1 week after the final dose.

• Sensitivity/Resistance - Superinfections:

Superinfections with Candida species other than C. albicans, which may have reduced susceptibility or resistance to fluconazole, have been reported. Alternative antifungal therapy may be required for such infections. Prescribers are advised to consider the prevalence of resistance in different Candida species when prescribing fluconazole.

• Skin - Dermatologic:

Rare cases of exfoliative skin disorders and drug reactions with eosinophilia and systemic symptoms (DRESS) have been reported during treatment with Fluconazole. Close monitoring is recommended, and the drug should be discontinued if lesions progress, particularly in patients with serious underlying diseases such as AIDS or malignancy.

When it comes to alcohol and fluconazole, it is generally advised to exercise caution and limit alcohol consumption. While there is no absolute prohibition against drinking alcohol while taking fluconazole, combining the two can have potential risks and interactions. Here are the alcohol-related warnings associated with the use of fluconazole:

• Increased side effects: Both fluconazole and alcohol can individually cause certain side effects, such as dizziness, drowsiness, and gastrointestinal disturbances. When used together, these effects may be intensified. Consuming alcohol while taking fluconazole can increase the likelihood and severity of these side effects.
• Liver function: Both fluconazole and alcohol can have an impact on liver function. Fluconazole is metabolized in the liver, and alcohol consumption can further strain the liver. Combining the two substances may increase the risk of liver damage or worsen existing liver conditions.
• Drug effectiveness: Alcohol can potentially interfere with the absorption and metabolism of fluconazole, affecting its effectiveness. It may lead to lower drug levels in the body, reducing its therapeutic effects.

Due to its secretion in human breast milk at levels comparable to plasma concentrations, the utilization of fluconazole is not advised for nursing mothers.

Pregnancy:

Teratogenic Effects - Category C

The use of Fluconazole in pregnant women is generally discouraged, except in cases where severe or potentially life-threatening fungal infections necessitate its use and the expected benefits outweigh the potential risks to the fetus. If this medication is employed during pregnancy or if a patient becomes pregnant while taking the drug, it is crucial to inform the patient about the potential risks to the fetus.

There have been reports and observational studies suggesting an elevated risk of spontaneous abortion and the occurrence of birth defects in infants whose mothers were treated with even low doses of fluconazole (as low as 150 mg) as a single or repeated dose during the first trimester.

Additionally, there have been instances of multiple congenital abnormalities in infants whose mothers received high-dose fluconazole therapy (400 mg/day to 800 mg/day) for coccidioidomycosis, an unapproved indication. In these cases, exposure to fluconazole began during the first trimester and continued for three months or longer.

Case reports have described a distinct and rare pattern of birth defects observed in infants whose mothers received high-dose fluconazole (400-800 mg/day) throughout most or all of the first trimester. These infants exhibited features such as brachycephaly, abnormal facial features, abnormal skull development, cleft palate, bowing of the femur, thin ribs and long bones, arthrogryposis, and congenital heart disease.

When taking fluconazole, there are a few food-related warnings to keep in mind:

• Grapefruit and grapefruit juice: It is generally recommended to avoid consuming grapefruit or grapefruit juice while taking fluconazole. Grapefruit can interfere with the metabolism of the drug, potentially leading to increased levels of fluconazole in the body. This can increase the risk of side effects and may affect the efficacy of the medication.
• Alcohol: It is advisable to avoid or limit alcohol consumption while taking fluconazole. Alcohol can add to the potential side effects of the medication, such as dizziness, drowsiness, and liver toxicity. Additionally, both fluconazole and alcohol can have an impact on liver function, so combining them may put additional strain on the liver.
• Food interactions: Fluconazole can be taken with or without food, as it is generally well-tolerated. However, certain food items, especially those high in fat or oil, may delay the absorption of fluconazole, potentially affecting its effectiveness.

The adverse reactions related to Fluconazole can be categorized as follows:

Common:

• Gastrointestinal disturbances (nausea, vomiting, abdominal pain, diarrhea)
• Headache
• Skin rash, itching, or hives
• Elevated liver enzymes
• Dizziness
• Fatigue
• Transient mild elevations in serum creatinine

Less common:

• Changes in taste sensation
• Indigestion or heartburn
• Loss of appetite
• Muscle or joint pain
• Sleep disturbances (insomnia or drowsiness)
• Dry mouth or metallic taste in the mouth
• Hair loss or thinning
• Sensitivity to sunlight (increased risk of sunburn)

Rare:

• Severe allergic reactions (difficulty breathing, swelling of the face or throat, severe rash)
• Liver damage or severe liver injury (jaundice, dark urine, pale stools)
• Severe skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis)
• Blood disorders (reduced red or white blood cell counts)
• Seizures or convulsions
• Hallucinations or changes in behavior
• Tendon inflammation or rupture
• Decreased potassium levels (hypokalemia)

Oral Contraceptives: In a study involving 10 healthy women, oral contraceptives were given before and after daily administration of fluconazole for 10 days. The study showed no significant difference in the levels of ethinyl estradiol or levonorgestrel after fluconazole administration. The average increase in ethinyl estradiol levels was 6%, ranging from -47% to 108%, and levonorgestrel levels increased by 17%, ranging from -33% to 141%.

Drug Interactions: When fluconazole is taken with medications metabolized by the cytochrome P450 system, it may lead to increased serum levels of those drugs. Caution should be exercised when co-administering fluconazole with such agents, and patients should be closely monitored.

Terfenadine: Interaction studies were conducted to evaluate the combination of terfenadine and fluconazole. The studies involved 6 healthy volunteers who received terfenadine and fluconazole. Fluconazole did not affect terfenadine plasma concentrations, but it increased the terfenadine acid metabolite AUC by 36%. No changes were observed in cardiac repolarization. However, another study showed that taking fluconazole at doses of 400 mg/day or higher significantly increased terfenadine plasma levels. Therefore, the use of fluconazole at doses of 400 mg or higher with terfenadine is not recommended, and patients should be closely monitored if they are prescribed lower doses of fluconazole with terfenadine.

Astemizole: There is limited information regarding the interaction between fluconazole and astemizole. However, caution should be exercised when co-administering these two drugs, and patients should be carefully monitored.

Cisapride: Co-administration of fluconazole and cisapride has been associated with cardiac events, including torsades de pointes. Therefore, caution should be exercised when using fluconazole and cisapride together, and patients should be closely monitored.

Theophylline: In a study involving 16 male volunteers, the pharmacokinetics of theophylline were evaluated before and after the administration of fluconazole. The study showed significant increases in theophylline AUC, Cmax, and half-life, along with a decrease in clearance. The mean increase in theophylline AUC was 21%, ranging from -5% to 48%. Patients receiving high doses of theophylline or at risk of theophylline toxicity should be monitored for signs of toxicity when taking fluconazole.

Cimetidine: Cimetidine administration resulted in a significant decrease in fluconazole AUC and Cmax. The mean decrease in fluconazole AUC was 13%, ranging from -3.4% to -31%, and Cmax decreased by 19%, ranging from -5% to -40%. However, when cimetidine was administered intravenously, it did not affect the bioavailability or pharmacokinetics of fluconazole.

Antacid: The administration of Maalox immediately before taking fluconazole had no effect on the absorption or elimination of fluconazole.

Cyclosporine: Before and after the administration of fluconazole 200 mg daily for 14 days, Cyclosporine AUC and Cmax were measured in 8 renal transplant patients who had been taking cyclosporine for at least 6 months at a stable dose for 6 weeks. The results showed a significant increase in cyclosporine AUC, Cmax, and Cmin (24-hour concentration), as well as a significant reduction in apparent oral clearance. The mean increase in AUC was 92% (ranging from 18% to 147%), Cmax increased by 60% (ranging from -5% to 133%), Cmin increased by 157% (ranging from 33% to 360%), and apparent oral clearance decreased by 45% (ranging from -15% to -60%). In patients with bone marrow transplants, fluconazole at a 100 mg daily dose did not affect cyclosporine pharmacokinetic levels. However, in renal transplant patients with or without renal impairment, fluconazole may significantly increase cyclosporine levels. Therefore, it is recommended to carefully monitor cyclosporine concentrations and serum creatinine in patients receiving both fluconazole and cyclosporine.

Tacrolimus: There have been reports of an interaction between fluconazole and tacrolimus, resulting in increased serum levels of tacrolimus. Nephrotoxicity has been observed in patients receiving both fluconazole and tacrolimus. Therefore, close monitoring is necessary for patients receiving concomitant treatment with tacrolimus and fluconazole.

Warfarin: In a study involving 13 normal male volunteers, the administration of fluconazole 200 mg daily for 14 days, followed by a single dose of warfarin (15 mg), led to a significant increase in prothrombin time response. The mean increase in the prothrombin time response was 7% (ranging from -2% to 13%). These changes indicate that prothrombin time may be prolonged in patients receiving both fluconazole and coumarin-type anticoagulants. Therefore, careful monitoring of prothrombin time is recommended in such patients.

Hydrochlorothiazide: When 100 mg of fluconazole was administered concomitantly with 50 mg of hydrochlorothiazide for 10 days in 13 normal volunteers, there was a significant increase in fluconazole AUC and Cmax compared to fluconazole alone. The mean increase in fluconazole AUC was 45% (ranging from 19% to 114%), and the mean increase in Cmax was 43% (ranging from 19% to 122%). These changes were attributed to a reduction in renal clearance of fluconazole by 30% (ranging from -10% to -50%).

The following are the side effects involving Fluconazole:

• Nausea
• Headache
• Abdominal pain
• Diarrhea
• Vomiting
• Rash
• Dizziness
• Fatigue
• Changes in taste sensation
• Upset stomach
• Indigestion
• Flatulence (excessive gas)
• Muscle or joint pain
• Hair loss
• Elevated liver enzymes (seen in blood tests)

Pregnancy:

Teratogenic Effects - Category C

The use of Fluconazole (fluconazole) in pregnant women is generally discouraged, except in cases where severe or potentially life-threatening fungal infections necessitate its use, and the expected benefits outweigh the potential risks to the fetus. If this medication is employed during pregnancy or if a patient becomes pregnant while taking the drug, it is crucial to inform the patient about the potential risks to the fetus.

There have been reports and observational studies suggesting an elevated risk of spontaneous abortion and the occurrence of birth defects in infants whose mothers were treated with even low doses of fluconazole (as low as 150 mg) as a single or repeated dose during the first trimester.

Additionally, there have been instances of multiple congenital abnormalities in infants whose mothers received high-dose fluconazole therapy (400 mg/day to 800 mg/day) for coccidioidomycosis, an unapproved indication. In these cases, exposure to fluconazole began during the first trimester and continued for three months or longer.

Case reports have described a distinct and rare pattern of birth defects observed in infants whose mothers received high-dose fluconazole (400-800 mg/day) throughout most or all of the first trimester. These infants exhibited features such as brachycephaly, abnormal facial features, abnormal skull development, cleft palate, bowing of the femur, thin ribs and long bones, arthrogryposis, and congenital heart disease.

Lactation:

Due to its secretion in human breast milk at levels comparable to plasma concentrations, the utilization of fluconazole is not advised for nursing mothers.

Pediatric:

A clinical trial conducted in an open-label, randomized, and controlled manner has demonstrated the effectiveness of Fluconazole in treating oropharyngeal candidiasis in children aged 6 months to 13 years.

In a study that did not involve a comparison with other treatments, Fluconazole exhibited efficacy in the treatment of candidemia (with 10 out of 11 patients being cured) and disseminated candidiasis (with 5 out of 6 patients showing either cure or improvement) in children.

Fluconazole has shown effectiveness in suppressing cryptococcal meningitis and/or disseminated cryptococcal infection in a compassionate study involving 6 children with life-threatening or serious mycosis. However, there is no available information regarding the effectiveness of fluconazole as the primary treatment for cryptococcal meningitis in children.

Furthermore, the usage of Fluconazole in children with cryptococcal meningitis, candidal esophagitis, or systemic candidal infections aligns with its approved use in similar indications for adults. This alignment is supported by pharmacokinetic studies in children, establishing that dosages for children are proportional to those for adults.

The safety of Fluconazole in children has been established based on a study involving 577 children ranging from 1 day to 17 years of age. These children received doses ranging from 1 to 15 mg/kg/day for periods of 1 to 1616 days. However, the efficacy of Fluconazole has not been established in infants below 6 months of age. Nonetheless, a small group of patients (29) aged between 1 day and 6 months have been safely treated with Fluconazole.

Geriatric Use:

Patients aged 65 years and older demonstrated good tolerance to Fluconazole.

Renal excretion is the primary method of clearance for fluconazole, with the drug being eliminated unchanged. Given that elderly patients are more likely to have reduced renal function, caution should be exercised, and dosage adjustments should be made based on creatinine clearance. Monitoring of renal function may also be beneficial.

In a limited number of elderly patients who received Fluconazole as prophylaxis following bone marrow transplant (BMT), there was a slightly higher incidence of discontinuation of the drug due to adverse reactions (4.3%) compared to younger patients (1.7%).

Physicians should be knowledgeable as well as vigilant about the treatment and identification of overdosage of Fluconazole.

To assist in eliminating any unabsorbed drug, activated charcoal may be administered. It is recommended to provide general supportive measures in cases of overdose. Symptoms of Fluconazole (fluconazole) overdosage have been reported, including hallucination and paranoid behavior.

In the event of an overdose, symptomatic treatment, along with supportive measures and, if necessary, gastric lavage, may be sufficient. Fluconazole is primarily eliminated through urine. Hemodialysis sessions lasting for three hours can reduce plasma levels by approximately 50%.

When mice and rats were exposed to very high doses of fluconazole, whether orally or intravenously, they exhibited various nonspecific signs of distress, such as reduced activity, ataxia, shallow respiration, ptosis, lacrimation, salivation, urinary incontinence, and cyanosis. Death occasionally followed clonic convulsions.

Pharmacodynamics

Fluconazole has demonstrated its ability to exhibit fungistatic activity against a wide range of microorganisms, effectively treating fungal infections. It has been shown to be effective against Candida albicans, Candida glabrata (with intermediate susceptibility in many strains), Candida parapsilosis, Candida tropicalis, and Cryptococcus neoformans. This activity is achieved through steroidal inhibition within fungal cells, disrupting cell wall synthesis, growth, and adhesion, thereby addressing fungal infections and their associated symptoms.

The fungistatic activity of fluconazole has also been observed in both normal and immunocompromised animal models, effectively treating systemic and intracranial fungal infections caused by Cryptococcus neoformans, as well as systemic infections caused by Candida albicans. It should be noted that resistant strains of microorganisms have been identified in cases where fluconazole was used as an antifungal therapy. Therefore, susceptibility testing is important when considering fluconazole as a treatment option.

Regarding concerns about the steroidal effects of fluconazole, studies have shown that it selectively inhibits fungal cytochrome P-450 enzymes rather than a variety of mammalian cytochrome P-450 enzymes. Daily administration of 50 mg fluconazole for up to 28 days has been found to have no impact on testosterone plasma concentrations in males or plasma concentrations of steroids in females of reproductive age. Clinical studies mentioned on the European Medicines Agency label have indicated that a dose of 200-400 mg fluconazole has no clinically significant effect on steroid levels or the ACTH-stimulated steroid response in healthy males. Additional studies have also confirmed the lack of significant effects of fluconazole on steroid levels.

Pharmacokinetics

Absorption

● Similar pharmacokinetic properties of fluconazole are observed regardless of whether it is administered intravenously or orally, and gastric pH does not seem to affect its absorption.

● The bioavailability of orally administered fluconazole is over 90% in normal volunteers compared to intravenous administration. The drug reaches systemic circulation without undergoing significant first-pass metabolism, allowing for dosage interchangeability between oral and intravenous routes.

● Peak plasma concentrations (Cmax) occur rapidly, typically within 1 to 2 hours after oral administration, with a terminal elimination half-life of approximately 30 hours. This extended half-life supports once-daily dosing for fungal infection treatment.

● A single oral dose of 400 mg fluconazole in fasted normal volunteers results in a mean Cmax of 6.72 μg/mL, and plasma concentrations and AUC exhibit dose proportionality for oral doses ranging from 50 to 400 mg.

● Oral bioavailability, as indicated by Cmax and AUC, is not affected by food when Fluconazole is administered as a single 50 mg capsule; however, Tmax (time to reach maximum concentration) is doubled.

● Steady-state concentrations are achieved within 5 to 10 days with once-daily oral doses of 50 to 400 mg. A loading dose twice the usual daily dose can expedite reaching steady-state plasma concentrations by the second day of treatment.

Distribution:

● The apparent volume of distribution of fluconazole is similar to total body water. Protein binding in plasma is low (11%-12%) and remains constant across tested concentrations without significant clinical implications. Fluconazole readily penetrates all body tissues and fluids studied.

● In normal volunteers, saliva concentrations of fluconazole are equal to or slightly higher than plasma concentrations, irrespective of dose, route, or duration of dosing. Patients with bronchiectasis exhibit sputum concentrations equal to plasma concentrations at 4 and 24 hours after a single 150 mg oral dose.

● In patients with fungal meningitis, fluconazole concentrations in the cerebrospinal fluid (CSF) are approximately 80% of plasma concentrations. Fluconazole freely enters erythrocytes, maintaining equivalent concentrations to plasma in whole blood.

● Fluconazole pharmacokinetics are not significantly affected by age alone but are notably influenced by decreased renal function. There is an inverse relationship between elimination half-life and creatinine clearance. Patients with impaired renal function may require dosage reduction. Hemodialysis reduces plasma concentrations by approximately 50% over a 3-hour session.

Elimination:

● Renal excretion is the primary route of clearance for fluconazole, with around 80% of the administered dose appearing unchanged in the urine. Radiolabeled fluconazole administration results in over 90% of the radioactivity being excreted in the urine, with approximately 11% attributed to metabolites. An additional 2% of total radioactivity is excreted in feces.

• Bergner R, Hoffmann M, Riedel KD, et al. Fluconazole dosing in continuous veno-venous haemofiltration (CVVHF): need for a high daily dose of 800 mg. Nephrol Dial Transplant. 2006;21(4):1019-1023. [PubMed 16311263] - This study explores the dosing of fluconazole in continuous veno-venous haemofiltration (CVVHF) and highlights the necessity of a high daily dose of 800 mg.
• Berl T, Wilner KD, Gardner M, et al. Pharmacokinetics of fluconazole in renal failure. J Am Soc Nephrol. 1995;6(2):242-247. [PubMed 7579091] - This study investigates the pharmacokinetics of fluconazole in patients with renal failure.
• Blair JE, Ampel NM. Coccidioidal meningitis. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed January 24, 2020. - This resource provides information on coccidioidal meningitis.
• Bodley V, Powers D. Long-term treatment of a breastfeeding mother with fluconazole-resolved nipple pain caused by yeast: a case study. J Hum Lact. 1997;13(4):307-311. doi:10.1177/089033449701300416 [PubMed 9429366] - This case study discusses the successful long-term treatment of yeast-induced nipple pain in a breastfeeding mother using fluconazole.
• Bradley JS, Nelson JD, Barnett ED, et al, eds. Nelson's Pediatric Microbial Therapy. 27th ed. American Academy of Pediatrics; 2021. - This edition of Nelson's Pediatric Microbial Therapy provides comprehensive information on pediatric microbial therapy.
• Bradley JS, Nelson JD, Kimberlin DK, et al, eds. Nelson's Pocket Book of Pediatric Antimicrobial Therapy. 28th ed. American Academy of Pediatrics; 2022. - This edition of Nelson's Pocket Book of Pediatric Antimicrobial Therapy offers a concise guide to pediatric antimicrobial therapy.
• Bradsher RW. Treatment of blastomycosis. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed January 21, 2020. - This resource discusses the treatment approaches for blastomycosis.
• Brammer KW, Farrow PR, Faulkner JK. Pharmacokinetics and tissue penetration of fluconazole in humans. Rev Infect Dis. 1990;12(suppl 3):S318-S326. doi:10.1093/clinids/12.supplement_3.s318 [PubMed 2184510] - This study explores the pharmacokinetics and tissue penetration of fluconazole in humans.
• Bratzler DW, Dellinger EP, Olsen KM, et al; American Society of Health-System Pharmacists; Infectious Diseases Society of America; Surgical Infection Society; Society for Healthcare Epidemiology of America. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Am J Health Syst Pharm. 2013;70(3):195-283. doi: 10.2146/ajhp120568. [PubMed 23327981] - This publication provides clinical practice guidelines for antimicrobial prophylaxis in surgical procedures.

1. https://go.drugbank.com/drugs/DB00196#
2. https://www.webmd.com/drugs/2/drug-3780-5052/fluconazole-oral/fluconazole-oral/details
3. https://www.pfizer.ca/files/Fluconazole_PM_EN.pdf
4. https://pdf.hres.ca/dpd_pm/00009113.PDF
5. https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019949s051lbl.pdf